In the United States, lung cancer is the second most common cancer for both men and women, and more people die from lung cancer than any other malignancy. The majority of these deaths arise from complications associated with metastatic disease. Unfortunately, the majority of lung cancers are found after the cancer has metastasized. Thus, it is imperative to identify the genes that regulate the development, and especially the metastasis, of lung cancers. To this end, we have identified novel miRNA that have altered expression in human lung adenocarcinoma cell lines and patients with non-small cell lung adenocarcinoma, the most common type of lung cancer. We have identified specific miRNA that contribute to lung adenocarcinoma growth, migration, and invasion. Notably, these miRNA have the opposite effect in breast carcinoma, highlighting a cellular context specificity for these genes. We propose to investigate the role of these miRNA in lung adenocarcinoma development and metastasis, as well as determine their utility as putative biomarkers for diagnosis and relapse prediction. In Aim 1, we will determine the role for specific miRNA in lung adenocarcinoma proliferation, migration, and invasion and the downstream proteins affected by them. In the Aim 2, we will determine the contribution of these novel genes in lung adenocarcinoma initiation and metastasis in vivo using mouse models. In Aim 3, we wil define the miRNA that predict human lung adenocarcinoma development and relapse and the proteins responsible for these processes. We will take multiple complementary approaches that utilize molecular biology, cell biology, biochemistry, and mouse modeling, as well as analysis of patient adenocarcinoma samples for our studies. These studies will significantly expand understanding of the molecular events that regulate the development and progression of lung adenocarcinoma. The results of the proposed experiments will also have clinical relevance by identifying new therapeutic targets and potential biomarkers for improved diagnosis and lung cancer outcome prediction. This work will be conducted at Vanderbilt University Medical Center, one of the nation's top biomedical research institutions. Vanderbilt provides an outstanding supportive training environment that will allow me to meet the goals of the research proposed and gain the training necessary to achieve my career goals in science. During my postdoctoral training here, I will gain critical knowledge and skills essential to my becoming a successful independent cancer biologist. There are many outstanding seminars and numerous professional development services and opportunities offered at Vanderbilt specifically for advancing postdoctoral fellows toward becoming independent investigators. My mentor and sponsor, Dr. Christine M. Eischen, will provide the personalized one-on-one training that will assist me in reaching my goals. Completing this National Research Service Award training plan will be essential in providing me with the skills needed for me to achieve my career goal of conducting research as an independent investigator studying epithelial cancer biology. PUBLIC HEALTH RELEVANCE: This project will investigate the function of newly discovered genes and their role in lung cancer, the leading cause of cancer deaths in the United States. These studies will expand our knowledge of lung cancer biology and the molecular events that regulate the development and progression of this disease. The results of the proposed experiments will likely identify new therapeutic targets and potential biomarkers for improved diagnosis and disease outcome prediction.